Renal Pathologic Findings in TAFRO Syndrome: Is There a Continuum Between Thrombotic Microangiopathy and Membranoproliferative Glomerulonephritis? A Case Report and Literature Review

Abstract

Background: TAFRO syndrome is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) that is characterized by thrombocytopenia, anasarca, fever and/or elevated serum C-reactive protein, renal dysfunction, and organomegaly. Case Presentation: A 28-year-old woman with fever, weight gain of 13 kgs, lower extremity edema, hepatosplenomegaly, and multicentric peripheral lymphadenopathy was referred to our center. Laboratory investigations revealed anemia, thrombocytopenia, creatinine at 1.19 mg/dL and hypoalbuminemia at 33 g/L. Proteinuria was measured at 2 g/day including albuminuria at 1.5 g/day. Urinary sediment examination found leukocyturia at 44,000/mL and hematuria at 645,000/mL. Vascular endothelial growth factor (VEGF) level was elevated. A cervical lymph node biopsy found features consistent with the mixed histopathological subtype of iMCD. A renal biopsy revealed a membranoproliferative glomerulonephritis (MPGN) pattern. We initiated 3 days of methylprednisolone pulse-therapy at 1,000 mg per day, followed by prednisone 1 mg/kg/day and evolution was favorable. Review of Literature: 19 iMCD patients with TAFRO syndrome had undergone a renal biopsy: 8 cases with author's diagnosis consistent with MPGN-like and 11 cases of thrombotic microangiopathy (TMA)-like glomerulopathy without fibrin thrombi in glomerular capillaries or arterioles and without typical biological signs. Clinical, biological, and outcome characteristics were similar between the cases described as having MPGN and TMA-like presentation. After a thorough review of histopathological descriptions for each case, MPGN lesions seems to be the consequences of chronic glomerular endothelial injury in persistent TMA. We suspect that VEGF and IL-6 play a key role in the physiopathology of the spectrum of renal involvement from TMA-like to MPGN observed in TAFRO syndrome. Conclusion: We present a Caucasian iMCD patient with TAFRO syndrome with renal insufficiency secondary to MPGN, which might be secondary to a chronic TMA-like disease. We suspect that there is a continuum between TMA and MPGN lesions in TAFRO syndrome favored by VEGF and IL-6.

A pediatric case of tocilizumab‐resistant TAFRO syndrome treated successfully with rituximab

“…Pediatricians need to be aware of TAFRO syndrome, because the number of cases with onset at a young age is increasing. 26,27 In conclusion, we achieved complete remission with rituximab in a pediatric case of TAFRO syndrome showing resistance to combined therapy including tocilizumab. Combining rituximab with anti-IL-6 agents may be an effective second-line treatment for TAFRO syndrome patients.…”

Acute Kidney Injury Caused by TAFRO Syndrome in a Chinese Patient: Efficacy of Long-Term Corticosteroids Combined with Bortezomib and Cyclophosphamide

“…Until 2019, 21 cases of TAFRO syndrome received renal biopsy worldwide. The 2 patterns described are most consistent with mesangial proliferative glomerular nephritis (MPGN) (42%) and a thrombotic microangiopathy (TMA)-like histology (58%), but without fibrin thrombi in the glomerular capillaries or arterioles [8]. Some of the MPGN-like patients had glomerulocapillary deposits while others showed weak or negative immunofluorescence results.…”

“…We note that another hematologic disorder called polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome has a very similar renal histology pattern to that of TAFRO patients [14]. Interestingly, patients with TAFRO syndrome, Castleman's disease patients demonstrating TMA-like lesions, and POEMS patients share the common disorder of a significantly elevated serum VEGF level [8,14,15]. It is speculated that high circulating levels of IL-6 and VEGF downregulate glomerular VEGF by podocytes via a negative-feedback mechanism, leading to the loss of glomerular endothelial cell fenestrations, just like those observed in patients receiving anti-VEGF agents and in those with pre-eclampsia [13,16].…”

“…The pathogenesis of acute oliguric renal failure in TAFRO syndrome remains unclear [3,[8][9][10][11]. Based on pathologic findings such as endothelial swelling, double contours of GBM, and thickening of the basement membrane, it is presumed that glomerular endothelial injuries could play a central role in the development of acute renal failure [3,8]. There are various types of renal histology reported in Castleman disease including AA-type amyloidosis, TMA, focal segmental glomerular sclerosis, interstitial nephritis, and even crescentic glomerulonephritis [12,13].…”

Kidney biopsy findings in two patients with TAFRO syndrome: case presentations and review of the literature

“…Both proteinuria and hematuria tended to be mild; nephrotic-range proteinuria was reported only in 1 patient, and only 1 patient died over the follow-up. In the literature review by Leurs A et al, outcomes tended to be worse when hemodialysis was necessary (44% of deaths compared to 5% when hemodialysis was not needed), without differences in outcomes between cases described as MPGN and TMA-like [ 31 ]. After hormone and monoclonal antibody treatment, the conditions of the two patients improved significantly, but they still did not achieve complete remission and needed further treatment and follow-up.…”